Stimuli-Responsive Polymer-Based Nanosystems for Cancer Theranostics.

Stimuli-responsive polymers can respond to internal stimuli, such as reactive oxygen species (ROS), glutathione (GSH), and pH, biological stimuli, such as enzymes, and external stimuli, such as lasers and ultrasound, etc., by changing their hydrophobicity/hydrophilicity, degradability, ionizability, etc., and thus have been widely used in biomedical applications. Due to the characteristics of the tumor microenvironment (TME), stimuli-responsive polymers that cater specifically to the TME have been extensively used to prepare smart nanovehicles for the targeted delivery of therapeutic and diagnostic agents to tumor tissues. Compared to conventional drug delivery nanosystems, TME-responsive nanosystems have many advantages, such as high sensitivity, broad applicability among different tumors, functional versatility, and improved biosafety. In recent years, a great deal of research has been devoted to engineering efficient stimuli-responsive polymeric nanosystems, and significant improvement has been made to both cancer diagnosis and therapy. In this review, we summarize some recent research advances involving the use of stimuli-responsive polymer nanocarriers in drug delivery, tumor imaging, therapy, and theranostics. Various chemical stimuli will be described in the context of stimuli-responsive nanosystems. Accordingly, the functional chemical groups responsible for the responsiveness and the strategies to incorporate these groups into the polymer will be discussed in detail. With the research on this topic expending at a fast pace, some innovative concepts, such as sequential and cascade drug release, NIR-II imaging, and multifunctional formulations, have emerged as popular strategies for enhanced performance, which will also be included here with up-to-date illustrations. We hope that this review will offer valuable insights for the selection and optimization of stimuli-responsive polymers to help accelerate their future applications in cancer diagnosis and treatment.

Bacterial outer membrane vesicles as drug delivery carrier for photodynamic anticancer therapy.

Photodynamic Therapy (PDT) is an effective tumor treatment strategy that not only induces photocytotoxicity to kill tumor cells directly but also activates the immune system in the body to generate tumor-specific immunity, preventing cancer metastasis and recurrence. However, some limitations of PDT limit the therapeutic efficacy in deep tumors. Previous studies have used different types of nanoparticles (NPs) as drug carriers of photosensitizers (PSs) to overcome the shortcomings of PDT and improve therapeutic efficacy. Among them, bacterial outer membrane vesicles (OMVs) have natural advantages as carriers for PS delivery. In addition to the targeted delivery of PSs into tumor cells, their unique immunogenicity helps them to serve as immune adjuvants to enhance the PDT-induced immune effect, providing new ideas for photodynamic anticancer therapy. Therefore, in this review, we will introduce the biogenesis and anticancer functions of OMVs and the research on them as drug delivery carriers in PDT. Finally, we also discuss the challenges and prospects of OMVs as a versatile drug delivery carrier for photodynamic anticancer therapy.

Microbiota and plant-derived vesicles that serve as therapeutic agents and delivery carriers to regulate metabolic syndrome.

The gut is a fundamental organ in controlling human health. Recently, researches showed that substances in the intestine can alter the course of many diseases through the intestinal epithelium, especially intestinal flora and exogenously ingested plant vesicles that can be transported over long distances to various organs. This article reviews the current knowledge on extracellular vesicles in modulating gut homeostasis, inflammatory response and numerous metabolic disease that share obesity as a co-morbidity. These complex systemic diseases that are difficult to cure, but can be managed by some bacterial and plant vesicles. Vesicles, due to their digestive stability and modifiable properties, have emerged as novel and targeted drug delivery vehicles for effective treatment of metabolic diseases.

Stable Discoidal Bicelles: Formulation, Characterization, and Functions.

Bicellar mixtures have been used as alignable membrane substrates under a magnetic field applicable for the structural characterization of membrane-associated proteins. Recently, it has shown that bicelles can serve as nanocarriers to effectively deliver hydrophobic therapeutic molecules to cancer cells with a three- to ten-fold enhancement compared to that of liposomes of a chemically identical composition. In this chapter, detailed preparation protocol, common structural characterization methods, the structural stability, the cellular uptake and a few unique functions of bicellar nanodiscs are discussed.

Research progress of yeast microcapsules as oral drug delivery carrier / 中国药房

As a natural drug delivery carrier with rough and porous surface and hollow core， yeast microcapsules have good safety， high targeting and high stability， and have excellent application prospects in oral drug delivery systems. Yeast cells can be treated and washed with acid-base and organic solvents to obtain loose and porous yeast microcapsules. Yeast microcapsules can encapsulate drugs through electrostatic interactions， passive diffusion， hydrophobic interaction and other methods. The surface of yeast microcapsules is mainly composed of β-glucan， which can maintain stability in the gastrointestinal environment； it can be recognized by the surface-related receptors of immune cells， thus activating the immune response， and can be transported to the lesion site with the movement of lymphocytes after being ingested. Yeast microcapsules are safe and very suitable for delivering vaccines， anti-inflammatory drugs， and anti-tumor drugs. They can not only achieve oral delivery of the aforementioned drugs， but also enhance drug efficacy and improve drug targeting. In the future， more research on systemic transport mechanisms or the development of more efficient combination drug delivery systems can be carried out to fully exhibit the clinical value of yeast microcapsules.

Corrigendum: Applications of chitosan and its derivatives in skin and soft tissue diseases.

[This corrects the article DOI: 10.3389/fbioe.2022.894667.].

Applications of Chitosan and its Derivatives in Skin and Soft Tissue Diseases.

Chitosan and its derivatives are bioactive molecules that have recently been used in various fields, especially in the medical field. The antibacterial, antitumor, and immunomodulatory properties of chitosan have been extensively studied. Chitosan can be used as a drug-delivery carrier in the form of hydrogels, sponges, microspheres, nanoparticles, and thin films to treat diseases, especially those of the skin and soft tissue such as injuries and lesions of the skin, muscles, blood vessels, and nerves. Chitosan can prevent and also treat soft tissue diseases by exerting diverse biological effects such as antibacterial, antitumor, antioxidant, and tissue regeneration effects. Owing to its antitumor properties, chitosan can be used as a targeted therapy to treat soft tissue tumors. Moreover, owing to its antibacterial and antioxidant properties, chitosan can be used in the prevention and treatment of soft tissue infections. Chitosan can stop the bleeding of open wounds by promoting platelet agglutination. It can also promote the regeneration of soft tissues such as the skin, muscles, and nerves. Drug-delivery carriers containing chitosan can be used as wound dressings to promote wound healing. This review summarizes the structure and biological characteristics of chitosan and its derivatives. The recent breakthroughs and future trends of chitosan and its derivatives in therapeutic effects and drug delivery functions including anti-infection, promotion of wound healing, tissue regeneration and anticancer on soft tissue diseases are elaborated.

Mannose-anchored quaternized chitosan/thiolated carboxymethyl chitosan composite NPs as mucoadhesive carrier for drug delivery.

There are various challenges for the mucosal delivery of drug, which is largely attributed to the absence of effective drug carriers that can make delivery to mucosal sites. In the present study, we aimed to synthesize bifunctional mucoadhesive nanoparticles (NPs) that could be used for mucosal delivery. N-2-Hydroxypropyl trimethyl ammonium chloride chitosan (M-N-2-HACC) was modified with D-mannose, and N-acetyl-L-cysteine (NAC) was immobilized on the carboxymethyl chitosan (N-CMCS). The electrostatic interaction between the two substances was used to produce mannose-modified thiolated chitosan NPs (M-N-2-HACC/N-CMCS NPs). The NPs showed a particle size of 196.72 ± 0.45 nm and zeta potential of 17.12 ± 0.50 mV. Moreover, it demonstrated high hydrophilicity, enduring drug release, stability, safety, and mucosal adhesion, which contributed to the effectiveness of mucosal administration. Additionally, the NPs could be instantly absorbed by macrophages. Collectively, these results suggested that M-N-2-HACC/N-CMCS NPs could be used as a promising candidate for mucosal delivery.

The Progress of Red Blood Cells Based Drug Delivery Systems / 中国输血杂志

Red blood cells(RBCs), as the most abundant types of blood cells in the blood, have several advantages as a drug delivery system due to their ultra-long circulation half-life, good biocompatibility, and biodegradability. To date, a variety of RBCs-based drug delivery techniques have been developed for the treatment of infection diseases, cancers, chronic diseases, and autoimmune diseases. This review summarized the progress of RBCs related drug delivery systems, and discussed the advantages and disadvantages of different loading methods and their pre-clinical application progress, promoting the research and development of drug delivery.

Promising Graphene-Based Nanomaterials and Their Biomedical Applications and Potential Risks: A Comprehensive Review.

Graphene-based nanomaterials (GBNs) have been the subject of research focus in the scientific community because of their excellent physical, chemical, electrical, mechanical, thermal, and optical properties. Several studies have been conducted on GBNs, and they have provided a detailed review and summary of various applications. However, comprehensive comments on biomedical applications and potential risks and strategies to reduce toxicity are limited. In this review, we systematically summarized the following aspects of GBNs in order to fill the gaps: (1) the history, synthesis methods, structural characteristics, and surface modification; (2) the latest advances in biomedical applications (including drug/gene delivery, biosensors, bioimaging, tissue engineering, phototherapy, and antibacterial activity); and (3) biocompatibility, potential risks (toxicity in vivo/vitro and effects on human health and the environment), and strategies to reduce toxicity. Moreover, we have analyzed the challenges to be overcome in order to enhance application of GBNs in the biomedical field.

A DNA Nanoraft-Based Cytokine Delivery Platform for Alleviation of Acute Kidney Injury.

Cytokine immunotherapy represents an attractive strategy to stimulate robust immune responses for renal injury repair in ischemic acute kidney injury (AKI). However, its clinical application is hindered by its nonspecificity to kidney, short circulation half-life, and severe side effects. An ideal cytokine immunotherapy for AKI requires preferential delivery of cytokines with accurate dosage to the kidney and sustained-release of cytokines to stimulate the immune responses. Herein, we developed a DNA nanoraft cytokine by precisely arranging interleukin-33 (IL-33) nanoarray on rectangle DNA origami, through which IL-33 can be preferentially delivered to the kidney for alleviation of AKI. A nanoraft carrying precisely quantified IL-33 predominantly accumulated in the kidney for up to 48 h. Long-term sustained-release of IL-33 from nanoraft induced rapid expansion of type 2 innate lymphoid cells (ILC 2s) and regulatory T cells (Tregs) and achieved better treatment efficiency compared to free IL-33 treatment. Thus, our study demonstrates that a nanoraft can serve as a structurally well-defined delivery platform for cytokine immunotherapy in ischemic AKI and other renal diseases.

Preparation of Magnetic-Luminescent Bifunctional Rapeseed Pod-Like Drug Delivery System for Sequential Release of Dual Drugs.

Drug delivery systems (DDSs) limited to a single function or single-drug loading are struggling to meet the requirements of clinical medical applications. It is of great significance to fabricate DDSs with multiple functions such as magnetic targeting or fluorescent labeling, as well as with multiple-drug loading for enhancing drug efficacy and accelerating actions. In this study, inspired by the dual-chamber structure of rapeseed pods, biomimetic magnetic-luminescent bifunctional drug delivery carriers (DDCs) of 1.9 ± 0.3 µm diameter and 19.6 ± 4.4 µm length for dual drug release were fabricated via double-needle electrospraying. Morphological images showed that the rapeseed pod-like DDCs had a rod-like morphology and Janus dual-chamber structure. Magnetic nanoparticles and luminescent materials were elaborately designed to be dispersed in two different chambers to endow the DDCs with excellent magnetic and luminescent properties. Synchronously, the Janus structure of DDCs promoted the luminescent intensity by at least threefold compared to single-chamber DDCs. The results of the hemolysis experiment and cytotoxicity assay suggested the great blood and cell compatibilities of DDCs. Further inspired by the core-shell structure of rapeseeds containing oil wrapped in rapeseed pods, DDCs were fabricated to carry benzimidazole molecules and doxorubicin@chitosan nanoparticles in different chambers, realizing the sequential release of benzimidazole within 12 h and of doxorubicin from day 3 to day 18. These rapeseed pod-like DDSs with excellent magnetic and luminescent properties and sequential release of dual drugs have potential for biomedical applications such as targeted drug delivery, bioimaging, and sustained treatment of diseases.

The Study of Ginger-Derived Extracellular Vesicles as a Natural Nanoscale Drug Carrier and Their Intestinal Absorption in Rats.

Extracellular vesicles have been widely used in drug delivery systems and clinical studies as a new natural nanoscale drug carrier. Most of these studies focused on the extracellular vesicles from animals, but few involved in the extracellular vesicles from edible plants. This study was the first to explore the potential and value of ginger-derived extracellular vesicles (GDEVs) as drug carrier by using the content ratio method and to further study their intestinal absorption in rats. In this experiment, GDEVs were extracted and purified by ultrahigh-speed centrifugation. GDEVs were saucer-like with a particle size of 70.09±19.24 nm and a zeta potential of -27.70±12.20 mV. In this experiment, high-performance liquid chromatography was used to explore the difference in gingerol content between GDEVs and ginger slices. Under the same mass, the contents of 6-gingerol (6G), 8-gingerol (8G), and 10-gingerol (10G) in GDEVs were 10.21-fold, 22.69-fold, and 32.36-fold of those in ginger slices, respectively. In this experiment, the absorption kinetics and absorption site of GDEVs were investigated using in situ single-pass intestinal perfusion method in rats. GDEVs could be absorbed by the small intestine in the concentration range of 15-60 mg/mL, and the absorption trend of different intestinal segments was duodenum > jejunum > ileum. These results indicated that GDEVs had good loading capacity and significant prospects as a carrier of the drug delivery system. At the same time, combining the oil-water partition coefficient (6G < 8G < 10G) of three gingerol compounds, we speculated that the loading capacity of GDEVs increased with the increase of the lipid solubility of the compounds. This study fully demonstrated the potential and value of ginger-derived extracellular vesicles as natural nanocarrier and provided an important reference for the further application of plant-derived extracellular vesicles in the drug delivery system.

Self-assembled heptamethine cyanine dye dimer as a novel theranostic drug delivery carrier for effective image-guided chemo-photothermal cancer therapy.

Near-infrared (NIR)-induced dye-based theranostic drug delivery carriers are used for critical image-guided chemo-photothermal cancer therapy. However, most carriers fail to deliver sufficient heat and fluorescence efficiently due to direct π-π stacking of the aromatic rings of the NIR dye and drug. In the work reported herein, we examined a self-assembled heptamethine cyanine dye dimer (CyD) with improved heat and fluorescence delivery that was developed by manipulating the unique structural and optical properties of the dimer. The H-aggregation of CyD in an aqueous solution generated a great amount of heat by transforming the energy of the excited electrons into non-radiative energy. Moreover, the disulfide bond of CyD assisted nanoparticles with a drug by minimizing the interaction between the NIR dye and drug, and also by releasing the drug in a redox environment. As a result, DOX encapsulated within CyD (CyD/DOX) showed strong heat generation and fluorescence imaging in tumor-bearing mice, allowing detection of the tumor site and inhibition of tumor growth by chemo-photothermal therapy. The multiplicity of features supplied by the newly developed CyD demonstrated the potential of CyD/DOX as an NIR dye-based theranostic drug-delivery carrier for effective chemo-photothermal cancer therapy.

Synthesis of Gum Arabic-g-polyaniline using diode laser.

Grafting of polyaniline (PANI) on Gum Arabic (GA) was carried out in the presence of ceric ammonium nitrate (CAN) under acidic conditions by diode laser as initiator. The grafting condition was optimized by varying the diode laser power, exposure time, concentrations of PANI, CAN, GA, reaction time and temperature were carefully optimized to achieve the highest percentage of grafting yield % GY (90%) and percentage of graft efficiency % GE (36%). The Fourier-transform infrared spectroscopy (FTIR), 1H NMR, X-ray Diffraction (XRD), Thermogravimetric Analysis (TGA), and Scanning electron micrographs (SEM) techniques have been used for the characterization of the produced graft copolymer GA-g-PANI, which used as drug delivery carrier to control cancer in brain. This study focused to new trends and latest developments in this area where diode laser was found to be efficient and, clean method for synthesis GA-g-PANI.

Combined Magnetoliposome Formation and Drug Loading in One Step for Efficient Alternating Current-Magnetic Field Remote-Controlled Drug Release.

We have developed a reproducible and facile one step strategy for the synthesis of doxorubicin loaded magnetoliposomes by using a thin-layer evaporation method. Liposomes of around 200 nm were made of 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) and iron oxide nanoparticles (NPs) with negative, positive, and hydrophobic surfaces that were incorporated outside, inside, or between the lipid bilayers, respectively. To characterize how NPs are incorporated in liposomes, advanced cryoTEM and atomic force microscope (AFM) techniques have been used. It was observed that only when the NPs are attached outside the liposomes, the membrane integrity is preserved (lipid melt transition shifts to 38.7 °C with high enthalpy 34.8 J/g) avoiding the leakage of the encapsulated drug while having good colloidal properties and the best heating efficiency under an alternating magnetic field (AMF). These magnetoliposomes were tested with two cancer cell lines, MDA-MB-231 and HeLa cells. First, 100% of cellular uptake was achieved with a high cell survival (above 80%), which is preserved (83%) for doxorubicin-loaded magnetoliposomes. Then, we demonstrate that doxorubicin release can be triggered by remote control, using a noninvasive external AMF for 1 h, leading to a cell survival reduction of 20%. Magnetic field conditions of 202 kHz and 30 mT seem to be enough to produce an effective heating to avoid drug degradation. In conclusion, these drug-loaded magnetoliposomes prepared in one step could be used for drug release on demand at a specific time and place, efficiently using an external AMF to reduce or even eliminate side effects.

[Construction of engineered exosomes with high loading efficiency of cellular endogenous proteins].

Exosomes have many advantages as natural drug delivery carriers, but their application is limited by the inefficient loading of intracellular drugs (such as proteins and nucleic acids). In this study, mCherry, a red fluorescent protein, was used as the endogenous cargo target. Through gene modification of donor cells and fusion expression of membrane localization elements (PB, CAAX, Palm and CD63), mCherry was specifically sorted into exosomes through biogenesis. Results show that CD63 had the highest sorting efficiency, followed by Palm. PB and CAAX led enrichment of mCherry on the plasma membrane, but not in exosomes. The approach provides an alternative to facilitate packaging of cargo by exosomes and thus to increase the efficient delivery of endogenous protein drugs.

One-Step Synthesis of Nitrogen-Doped Hydrophilic Mesoporous Carbons from Chitosan-Based Triconstituent System for Drug Release.

In situ nitrogen-doped hydrophilic mesoporous carbon spheres with different carbon-to-silicon (C/Si) ratios (NMCs-x/3, x = 5, 6, 7, and 8) were prepared by one-step method coupled with a spray drying and carbonizing technique, in which triblock copolymer (F127) and tetraethyl orthosilicate (TEOS) were used as template agents, and biocompatible chitosan (CS) was used as the carbon source and nitrogen source. These carbon materials were characterized by TG, BET, XRD, Raman, FTIR, TEM, XPS, and contact angle measuring device. The adsorption and release properties of mesoporous carbon materials for the poorly soluble antitumor drug hydroxycamptothecin (HCPT) were investigated. Results showed that nanospherical mesoporous carbon materials were successfully prepared with high specific surface area (2061.6 m2/g), narrowly pore size distribution (2.01-3.65 nm), and high nitrogen content (4.75-6.04%). Those NMCs-x showed a satisfactory hydrophilicity, which gradually increased with the increasing of surface N content. And the better hydrophilicity of NMCs-x was, the larger adsorption capacity for HCPT. The absorption capacity of NMCs-x towards HCPT was in the following orders: qNMCs-5/3 > qNMCs-6/3 > qNMCs-7/3 > qNMCs-8/3. NMCs-5/3 had the largest saturated adsorption capacity of HCPT (1013.51 mg g-1) and higher dissolution rate (93.75%).

Chitosan-based (Nano)materials for Novel Biomedical Applications.

Chitosan-based nanomaterials have attracted significant attention in the biomedical field because of their unique biodegradable, biocompatible, non-toxic, and antimicrobial nature. Multiple perspectives of the proposed antibacterial effect and mode of action of chitosan-based nanomaterials are reviewed. Chitosan is presented as an ideal biomaterial for antimicrobial wound dressings that can either be fabricated alone in its native form or upgraded and incorporated with antibiotics, metallic antimicrobial particles, natural compounds and extracts in order to increase the antimicrobial effect. Since chitosan and its derivatives can enhance drug permeability across the blood-brain barrier, they can be also used as effective brain drug delivery carriers. Some of the recent chitosan formulations for brain uptake of various drugs are presented. The use of chitosan and its derivatives in other biomedical applications is also briefly discussed.

Design and performance of sericin/poly(vinyl alcohol) hydrogel as a drug delivery carrier for potential wound dressing application.

Developing a non-toxic, super-absorbent and antibacterial hydrogel as a skin wound dressing is of significant importance. Sericin hydrogel is an ideal dressing material as it has excellent biocompatibility, biodegradability, moisture retention, high affinity to biomolecules, self-healing and promoting cell proliferation activity. Here, we blended silk sericin (SS) with poly(vinyl alcohol) (PVA) to prepare a SS/PVA hydrogel through repetitive freeze-thawing. The photoluminescence of SS/PVA hydrogel indicated PVA was well blended with sericin. SS/PVA hydrogel showed excellent hydrophilicity and swelling behavior for its porous structure. PVA blending effectively improved the thermostability of sericin and enhanced the mechanical property of sericin, but did not affect the crystallinity of sericin and PVA. SS/PVA hydrogel exhibited the ability to load and release small molecule drugs and silver nanoparticles. Cytotoxicity and immuno-toxicity assays suggested the gentamicin loaded SS/PVA hydrogel had excellent cytocompatibility on mammalian cells. Bacterial inhibition assay and wound infection model demonstrated the gentamicin loaded SS/PVA hydrogel could effectively inhibit bacterial growth, thus maintain cells viability. This novel hydrogel with antimicrobial activity has shown great potential in wound dressing.